SUMMARY The occurrence of certain AIDS-associated opportunistic infectious diseases combined with the emergence of multidrug-resistant strains of bacteria and fungi has produced an urgent need for new approaches to antimicrobial therapy. Five years ago we first suggested the use of radioimmunotherapy (RIT) as a novel modality for treatment of opportunistic infections whereby radiolabeled specific monoclonal antibodies (mAbs) are used to deliver microbicidal radiation to pathogens. This application proposes to further investigate the potential of RIT in treatment of CN infection by utilizing longer lived radionuclides with more powerful nuclear emissions, and mAbs with various isotypes which might combate infections with high inoculum and as well as to identify the contribution of immune system towards RIT efficacy in immunocompetent and immunocompromised hosts which would allow to develop RIT clinical protocols aimed at specific patient populations. We hypothesize that radiolabeling capsule binding mAbs with longer-lived radionuclides with the variety of energies would permit delivery of higher fungicidal doses of radiation to the sites of the infection in the host. We propose to utilize Lead-212/Bismuth-212 parent- daughter pair as an -emitter and radiolanthanides - as -emitters. We also hypothesize that if the binding constants of IgGs and IgAs mAbs to glucoroxylomannan are close to each other - mAbs with IgA isotype will be more efficient in RIT of CN as they will be able to deliver their radioactive cargo closer to the cell body containing radiation-sensitive DNA and cellular machinery. We already possess the family of mAbs with the same variable region but various isotypes. Finally, based on our experimental observations that the profound effects of CN infection on the immune system make infection RIT outcomes much more dependent on immune status than in cancer RIT - we hypothesize that immune system plays a significant role in the outcome of infection RIT and we are planning to prove this hypothesis by evaluating contribution of neutrophils, cytokines, complement and cellular immunity to the RIT. The proposed research will facilitate clinical introduction of RIT of opportunistic CN infection. Understanding of immune mechanisms involved in the RIT outcomes will help to devise clinical protocols with expanded therapeutic window for treatment of patients in different stages of the disease.